Calibration of blood gas analyzers or their sensors is carried out at predetermined time intervals, using calibration fluids that are kept in the analyzer in disposable containers. The amount of fluid held in these containers is usually sufficient for a multitude of calibration measurements.
Quality control of blood gas analyzers requires measurement of control fluids at regular intervals. Comparing the obtained measurement values with the target values for the analytes O2, CO2, pH, etc. of the control fluid will permit evaluation of the quality of the sensors and the measurement system. In general each control measurement uses one ampoule of control fluid. As a consequence, quality controls are cost-intensive. It is therefore desirable to provide containers from which control fluid can repeatedly be aspired and measured.
Although only the values of the analytes in the respective fluids are relevant for calibration or control measurements, the provisions for storage and delivery of these fluids are of primary importance. This is particularly true for the analyte values in blood gas analysis, since these are based on the concentrations of gases dissolved in the fluid (CO2, O2). Gases dissolved in the fluid undergo an exchange with the gas phase contacting the fluid in accordance with Henry's law. A reference fluid stored in a container, which is not sealed gas-tightly and thus is in contact with the ambient atmosphere, will unavoidably suffer a change in analyte values as time passes.
U.S. Pat. No. 3,681,255 (Wilfore) and U.S. Pat. No. 4,871,439 (Enzer et al.) disclose designs of “headspace-free” bags for the storage of calibration and control fluids. The fluids are filled into gas-tight, flexible bags without a gas phase, avoiding the formation of gas bubbles. An exchange between the dissolved gases and a gas phase is thus inhibited. Multiple withdrawal of great amounts of fluid during operation over time does not pose a problem, since the bags are connected to the fittings of the analyzer via tubes and successive withdrawals of fluid will only cause a decrease in volume of the flexible bags.
The above design has the disadvantage that oxygen is not sufficiently stabilized. Since only a small amount of oxygen is dissolved in the aqueous fluid, even a slight decrease of oxygen in the fluid causes a large change in the analyte value for the blood gas parameter pO2, and no stable or predictable target value for this parameter can be ensured over the storage period of the container. A loss of small amounts of oxygen in the solution occurs for instance through reaction of oxygen either with plastic coating material or with substances in the solution with which oxygen reacts as time passes. A further cause for the decrease in oxygen content is slow diffusion through the seams of the container.
Solutions of the stabilization problem of oxygen in headspace-free bags are described in U.S. Pat. No. 4,116,336 (Sorensen et al.), U.S. Pat. No. 5,780,302 (Conlon et al.), and U.S. Pat. No. 7,378,006 (Shin et al.).
U.S. Pat. No. 5,780,302 describes a method for stabilizing O2 by means of packaging the solution in a container made of a laminate. The laminate consists of (a) an inner layer (heat sealable polymer consisting of polypropylene), (b) an intermediate layer (aluminum), (c) an outer layer (polyester nylon and a lacquer coating), and (d) an access device which is located entirely within the container.
U.S. Pat. No. 7,378,006 discloses the addition of choline to the fluid for the stabilizing of pO2 values.
U.S. Pat. No. 6,405,872 (Ruether et al.) proposes for multiple withdrawal of tonometered gas-equilibrated fluids the use of gas-tight, flexible containers with a gas phase acting as a gas reservoir for stabilizing the gas values. The container is connected to the fittings of the analyzer via a line. A disadvantage of this proposal is the fact that, depending on the size of the container and due to the physical circumstances mentioned above, the (new) equilibration following rapid temperature or pressure changes will be slow and require some hours.
A concept for the stabilization of oxygen in control fluids, which are contained in glass ampoules, is based on contact of the fluid with a gas phase within the ampoule. The large amount of oxygen in the gas phase stabilizes the comparatively lower and therefore sensitive oxygen content in a purely aqueous or saline control fluid. A disadvantage of such a gas phase is that the oxygen content of the solution is temperature-sensitive due to the temperature dependence of Henry's constant. The equilibrium distribution of the individual components between gas phase and solution at various temperatures can be computed for small volumes in glass ampoules and can also be found by experiment. Based on the equilibrium distribution target values can be predicted for the blood gas parameters. In known ampoules the volumes of fluid and gas phase are roughly equal and there exists relative to the fluid volume a large phase boundary surface, which due to the rigidity of the vertically standing ampoule is constant. This will provide sufficient predictability of the effective gas values even when temperature changes. The use of ampoules has the economic disadvantage that one whole ampoule is needed for each QC or control measurement, because after opening of the ampoule the gas values will rapidly change due to interaction with the ambient atmosphere.
In contrast to the conditions prevailing if small, rigid ampoules of 1-2 ml content are used as mentioned above, in larger amounts of fluid the equilibrium distribution will take several hours to readjust itself. In the case of fluid volumes of 150 to 300 ml and a surface of 15 cm2 (i.e., a head of liquid of 10-20 cm) the equilibration time or readjustment time, that is the time needed to establish a sufficiently accurate homogeneous distribution of gas concentrations within the fluid after rapid changes of temperature or pressure, lies in the vicinity of 36 hours. After inserting a new container of reference fluids into the analyzer or after prolonged stand-by periods of the analyzer under instable temperature conditions there will result delays in operation or measurement errors.
Cartridges comprising one or more gastight containers, for instance bags made of gas-impermeable plastic material, which are exchangably inserted into the analyzer, present an obvious choice for calibration or control fluids (reference fluids).
It is however necessary to stabilize the oxygen dissolved in the fluid, which serves as target value or analyte for the parameter of oxygen partial pressure (pO2) present in the calibration or control fluid.
As mentioned above this can be achieved by including a gas space (head space) in the bag. The large amount of oxygen in the gas phase stabilizes the comparatively lower and thus more sensitive oxygen content of a purely aqueous or saline control fluid. Due to the temperature dependence of Henry's constant a certain temperature sensitivity of the oxygen content of the solution must be allowed for, however. This is counterbalanced insofar as the gas exchange between aqueous solution and gas phase is purely diffusion based and equilibrium is attained only after a period of some hours, in contrast to the situation given in small ampoules as mentioned above.
Flexible containers include the bags as described in U.S. Pat. No. 6,405,872. These bags consist of a multilayer, gas-tight sheet material that is welded at the edges. Past experience has shown that very good storage stability of reference fluids filled into such bags can be achieved by using a simple commercially available aluminium laminate with polyethylene coating.
In the flexible bags according to U.S. Pat. No. 6,405,872 a first part of volume is occupied by the tonometered fluid containing at least one dissolved gas component. A second part of volume of the flexible bag is provided for the gas phase, which comprises at least the gas component dissolved in the fluid. The surface of the fluid separates the gas phase from the fluid and acts as an exchange surface. Since the volume occupied by the fluid plus the volume of the gas phase together is less than the maximum filling volume of the flexible bag, the interior pressure in the bag equals the ambient atmospheric pressure, even when temperature and pressure changes occur (within predetermined limits).
According to European Patent No. 2 077 452 B1, fluid withdrawal from the flexible bag may be performed with the use of a multi-way valve with at least two valve positions controlled by the analyzer, which may be provided at the entry point of the corresponding connecting line into the bag. The first valve position establishes a connection between the connecting line to the analyzer and the flexible bag while the second valve position closes the flexible bag and establishes a flow connection between an air source, e.g., ambient air and the connecting line.
U.S. Pat. No. 7,188,993 B1 (Howe et al.) discloses a method and apparatus for resonant vibration mixing of fluids, solid particles and/or gases. The apparatus has three independently movable massive bodies connected by spring systems in a rigid housing, where one of these massive bodies, i.e., the oscillator body, is induced to vibrate by an electric motor. A mixing chamber receiving the substances to be mixed is attached to one of the other bodies. An embodiment of the invention describes the use of the apparatus for creating a mixture of a fluid and a gas to produce gasified media, in which the gas is stored in the fluid for a period of time in the form of microsized bubbles. Due to the creation of bubbles in the fluid such methods are not suitable for accelerating equilibration of reference fluids of an analyzer.
U.S. Patent Application Publication No. 2011/0065084 A1 (Rao et al.) discloses a system and a method for the measuring and controlling of oxygen in a rigid-walled culture vessel containing cells in a culture medium and a gas phase. To the interior wall of the culture vessel is attached an optical oxygen sensor in contact with the culture medium, which is externally excited by a light source and monitored by a photodetector whose signal is fed to a control unit. On the outer wall of the culture vessel there is attached a vibration mixer, which imparts vibration energy to the rigid-walled culture vessel based on the feedback of the oxygen sensor. Thus oxygen transport is increased and fast equilibration between culture medium and the gas phase is attained.